Modifying polymer properties with penetrants in the fabrication of bioresorbable scaffolds

ABSTRACT

Methods of fabricating a bioresorbable polymer scaffold are disclosed including a step of inducing crystallization in a bioresorbable polymer construct through exposure to a liquid penetrant.

This application is a continuation of application Ser. No. 13/556,986filed Jul. 24, 2012 which is incorporated by reference herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates polymeric medical devices, in particular,bioresorbable stents or stent scaffoldings.

2. Description of the State of the Art

This invention relates to radially expandable endoprostheses that areadapted to be implanted in a bodily lumen. An “endoprosthesis”corresponds to an artificial device that is placed inside the body. A“lumen” refers to a cavity of a tubular organ such as a blood vessel. Astent is an example of such an endoprosthesis. Stents are generallycylindrically shaped devices that function to hold open and sometimesexpand a segment of a blood vessel or other anatomical lumen such asurinary tracts and bile ducts. Stents are often used in the treatment ofatherosclerotic stenosis in blood vessels. “Stenosis” refers to anarrowing or constriction of a bodily passage or orifice. In suchtreatments, stents reinforce body vessels and prevent restenosisfollowing angioplasty in the vascular system. “Restenosis” refers to thereoccurrence of stenosis in a blood vessel or heart valve after it hasbeen treated (as by balloon angioplasty, stenting, or valvuloplasty)with apparent success.

Stents are typically composed of a scaffold or scaffolding that includesa pattern or network of interconnecting structural elements or struts,formed from wires, tubes, or sheets of material rolled into acylindrical shape. This scaffolding gets its name because it physicallyholds open and, if desired, expands the wall of the passageway.Typically, stents are capable of being compressed or crimped onto acatheter so that they can be delivered to and deployed at a treatmentsite.

Delivery includes inserting the stent through small lumens using acatheter and transporting it to the treatment site. Deployment includesexpanding the stent to a larger diameter once it is at the desiredlocation. Mechanical intervention with stents has reduced the rate ofrestenosis as compared to balloon angioplasty. Yet, restenosis remains asignificant problem. When restenosis does occur in the stented segment,its treatment can be challenging, as clinical options are more limitedthan for those lesions that were treated solely with a balloon.

Stents are used not only for mechanical intervention but also asvehicles for providing biological therapy. Biological therapy usesmedicated stents to locally administer a therapeutic substance. Amedicated stent may be fabricated by coating the surface of either ametallic or polymeric scaffold with a polymeric carrier that includes anactive or bioactive agent or drug. Polymeric scaffolds may also serve asa carrier of an active agent or drug. An active agent or drug may alsobe included on a scaffold without being incorporated into a polymericcarrier.

The stent must be able to satisfy a number of mechanical requirements.The stent must be capable of withstanding the structural loads, namelyradial compressive forces, imposed on the scaffold as it supports thewalls of a vessel. Therefore, a stent must possess adequate radialstrength. Radial strength, which is the ability of a stent to resistradial compressive forces, relates to a stent's radial yield strengthand radial stiffness around a circumferential direction of the stent. Astent's “radial yield strength” or “radial strength” (for purposes ofthis application) may be understood as the compressive loading, which ifexceeded, creates a yield stress condition resulting in the stentdiameter not returning to its unloaded diameter, i.e., there isirrecoverable deformation of the stent. When the radial yield strengthis exceeded the stent is expected to yield more severely and only aminimal force is required to cause major deformation. Radial strength ismeasured either by applying a compressive load to a stent between flatplates or by applying an inwardly-directed radial load to the stent.

Once expanded, the stent must adequately maintain its size and shapethroughout its service life despite the various forces that may come tobear on it, including the cyclic loading induced by the beating heart.For example, a radially directed force may tend to cause a stent torecoil inward. In addition, the stent must possess sufficientflexibility to allow for crimping, expansion, and cyclic loading.

Some treatments with stents require its presence for only a limitedperiod of time. Once treatment is complete, which may include structuraltissue support and/or drug delivery, it may be desirable for the stentto be removed or disappear from the treatment location. One way ofhaving a stent disappear may be by fabricating a stent in whole or inpart from materials that erodes or disintegrate through exposure toconditions within the body. Stents fabricated from biodegradable,bioabsorbable, bioresorbable, and/or bioerodable materials such asbioabsorbable polymers can be designed to completely erode only afterthe clinical need for them has ended.

A drawback of bioresorbable polymers as compared to metals used forstent is that polymers typically have lower strength. Therefore, animportant aspect in fabricating bioresorbable polymer scaffolds isprocessing methods that increase the strength of the polymer.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference, and as if eachsaid individual publication or patent application was fully set forth,including any figures, herein.

SUMMARY OF THE INVENTION

Embodiments of the present invention include a method of fabricating abioresorbable stent scaffold comprising: providing tube made of abioresorbable polymer; exposing the tube to a solvent for a period oftime, wherein the solvent is absorbed into the bioresorbable polymerwhich increases a crystallinity of the bioresorbable polymer; andfabricating a scaffold having a pattern of interconnected struts fromthe exposed tube.

Embodiments of the present invention include a method of fabricating abioresorbable stent scaffold comprising: providing tube made of abioresorbable polymer; exposing the tube to a fluid comprising methanolfor a period of time, wherein the fluid is absorbed into thebioresorbable polymer which increases a crystallinity of thebioresorbable polymer; and fabricating a scaffold having a pattern ofinterconnected struts from the exposed tube.

Embodiments of the present invention include a method of fabricating abioresorbable stent scaffold comprising: providing tube made of abioresorbable polymer; exposing the tube to a fluid comprising methanolfor a period of time, wherein the solvent is absorbed into thebioresorbable polymer and increases a flexibility of the bioresorbablepolymer; radially expanding the exposed tube comprising the absorbedfluid from a first diameter to a second diameter; and fabricating ascaffold having a pattern of interconnected struts from the radiallyexpanded tube.

Embodiments of the present invention include a method comprising:providing a scaffold made of a bioresorbable polymer comprising absorbedpenetrant that decreases a modulus and increases an elongation at breakof the bioresorbable polymer, wherein the penetrant is a fluidcomprising methanol or ethanol; and crimping the scaffold from a firstdiameter to a reduced diameter over a delivery balloon.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a stent.

FIG. 2 shows the average sorption uptake value, weight change in %, fromthe amorphous and semi-crystalline PLLA samples soaked in water.

FIG. 3 shows the average desorption value, weight change in %, from theamorphous and semi-crystalline PLLA samples soaked in water.

FIG. 4 shows the average sorption uptake value, weight change in %, as afunction of the square root of time (h)^(1/2) from the amorphous andsemi-crystalline PLLA samples soaked in methanol.

FIG. 5 shows the average desorption value, weight change in %, as afunction of the square root of time (h)^(1/2) from the amorphous andsemi-crystalline PLLA samples soaked in methanol.

FIG. 6 shows the average sorption uptake value, weight change in %, as afunction of the square root of time (h)^(1/2) from the amorphous andsemi-crystalline PLLA samples soaked in ethanol.

FIG. 7 shows the average desorption value, weight change in %, as afunction of the square root of time (h)^(1/2) from the amorphous andsemi-crystalline PLLA samples soaked in Ethanol.

FIG. 8 depicts an image of water-, ethanol-, and methanol droplet onsemi-crystalline samples shows the affinity between the solvents thematerial.

FIG. 9 shows the DSC thermograms of water soaked amorphous PLLA samples.

FIG. 10 shows the DSC thermograms of ethanol soaked amorphous PLLAsamples.

FIG. 11 shows the DSC thermograms of methanol soaked amorphous PLLAsamples.

FIG. 12 shows DSC thermograms of the dried methanol soaked amorphousPLLA samples.

FIG. 13 shows the DSC thermograms of water soaked semi-crystalline PLLAsamples.

FIG. 14 shows the DSC thermograms of ethanol soaked semi-crystallinePLLA samples.

FIG. 15 shows the DSC thermograms of methanol soaked semi-crystallinePLLA samples.

FIG. 16 shows the WAXD pattern of dry amorphous sample without soakingat the bottom of the FIG. followed by water-, ethanol-, and methanolsoaked amorphous PLLA samples.

FIG. 17 shows the WAXD pattern of dry semi-crystalline sample withoutsoaking at the bottom of the FIG. followed by water-, ethanol-, andmethanol soaked PLLA samples.

FIG. 18 depicts the intercept method of area change as a function oftemperature to assess the fictive temperature.

DETAILED DESCRIPTION OF THE INVENTION

The methods described herein are generally applicable to any amorphousor semi-crystalline polymeric implantable medical device, especiallythose that have load bearing portions when in use or have portions thatundergo deformation during use. In particular, the methods can beapplied to tubular implantable medical devices such as self-expandablestents, balloon-expandable stents, and stent-grafts.

FIG. 1 illustrates a portion of an exemplary stent or scaffold pattern100. The pattern 100 of FIG. 1 represents a tubular scaffold structureso that an axis A-A is parallel to the central or longitudinal axis ofthe scaffold. FIG. 1 shows the scaffold in a state prior to crimping orafter deployment. Pattern 100 is composed of a plurality of ring struts102 and link struts 104. The ring struts 102 forms a plurality ofcylindrical rings, for example, rings 106 and 108, arranged about thecylindrical axis A-A. The rings are connected by the link struts 104.The scaffold comprises an open framework of struts and links that definea generally tubular body with gaps 110 in the body defined by rings andstruts. The cylindrical tube of FIG. 1 may be formed into this openframework of struts and links described by a laser cutting device thatcuts such a pattern into a thin-walled tube that may initially have nogaps in the tube wall.

A stent such as stent 100 may be fabricated from a polymeric tube or asheet by rolling and bonding the sheet to form the tube. A tube or sheetcan be formed by extrusion or injection molding. A stent pattern, suchas the one pictured in FIG. 1, can be formed in a tube or sheet with atechnique such as laser cutting or chemical etching. The stent can thenbe crimped on to a balloon or catheter for delivery into a bodily lumen.

A stent or scaffold of the present invention can be made partially orcompletely from a biodegradable, bioresorbable, and bioabsorbablepolymer. The stent can also be made in part of a biostable polymer. Apolymer for use in fabricating stent can be biostable, bioresorbable,bioabsorbable, biodegradable or bioerodable. Biostable refers topolymers that are not biodegradable. The terms biodegradable,bioresorbable, bioabsorbable, and bioerodable are used interchangeablyand refer to polymers that are capable of being completely degradedand/or eroded into different degrees of molecular levels when exposed tobodily fluids such as blood and can be gradually resorbed, absorbed,and/or eliminated by the body. The processes of breaking down andabsorption of the polymer can be caused by, for example, hydrolysis andmetabolic processes.

Exemplary embodiments of stent patterns for coronary and otherapplications is described in U.S. application Ser. No. 12/447,758 (US2010/0004735) to Yang & Jow, et al. Other examples of suitable stentpatterns are found in US 2008/0275537. The thickness of the scaffold maybe between 130 and 180 microns. An exemplary cross-section of the strutsof a scaffold is 150×150 microns. The scaffolds may have a pre-crimpingor an as-fabricated diameter of between 2.5 to 4 mm, more narrowly, 3 to3.5 mm, or at or about 2.5 mm, 3 mm, or 3.5 mm. The scaffold can becrimped from the as-fabricated diameter over a semi-compliant ornon-compliant balloon to a crimped profile of about a 1.8 to 2.2 mmdiameter (e.g., 2 mm). The scaffold may be deployed to a diameter ofbetween about 3 mm and 4 mm.

Exemplary stent scaffold patterns for the superficial femoral artery(SFA) and other applications are disclosed in US2011/0190872,US2011/0190871, and U.S. patent application Ser. No. 13/549,366. Ascompared to coronary stents, a peripheral (SFA) stent scaffold usuallyhas lengths of between about 36 and 60 mm or even between 40 and 200 mmwhen implanted in the superficial femoral artery, as an example. Thescaffold for SFA may have a pre-crimping diameter of between 5-10 mm, ormore narrowly 6-8 mm, and can possess a desired pinching stiffness whileretaining at least a 80% recoverability from a 50% crush. The scaffoldfor SFA may have a wall thickness of about 0.008″ to 0.014″ andconfigured for being deployed by a non-compliant balloon, e.g., 6.5 mmdiameter, from about a 1.8 to 2.2 mm diameter (e.g., 2 mm) crimpedprofile. The SFA scaffold may be deployed to a diameter of between about4 mm and 7 mm.

Such scaffolds may further include a polymer coating which optionallyincludes a drug. The coating may be conformal (around the perimeter ofthe scaffold) and may be 2-8 microns thick. In other embodimentsdescribed herein, the scaffolds may be made partly out of the composite.

Bioresorbable stents can be useful for treatment of various types ofbodily lumens including the coronary artery, superficial femoral artery,popliteal artery, neural vessels, and the sinuses. In general, thesetreatments require the stent to provide mechanical support to the vesselfor a period of time and then desirably to absorb away and disappearfrom the implant site. The important properties of a bioabsorbable stentor scaffolding include mechanical and degradation properties. Themechanical requirements include high radial strength, high radialstiffness, and high fracture toughness. The degradation propertiesinclude the absorption profile, for example, the change in molecularweight, radial strength, and mass with time.

With respect to radial strength and stiffness, a stent should havesufficient radial strength and/or stiffness to withstand structuralloads, namely radial compressive forces, imposed on the stent so thatthe stent can support the walls of a vessel at a selected diameter for adesired time period. A polymeric stent with adequate radial strengthand/or stiffness enables the stent to maintain a lumen at a desireddiameter for a sufficient period of time after implantation into avessel.

In addition, the stent should possess sufficient toughness or resistanceto fracture to allow for crimping, expansion, and cyclic loading withoutfracture or cracking that would compromise the function of the stent.The toughness or resistance to fracture can be characterized for amaterial by the elongation at break and for a scaffold by the number anddegree of cracks in a scaffold during use, such as after crimping ordeployment. These aspects of the use of the stent involve deformation ofvarious hinge portions of the structural elements of the scaffold.

Some bioresorbable polymers, for example, semi-crystalline polymers, arestiff or rigid under physiological conditions within a human body andhave been shown to be promising for use as a scaffold material.Specifically, polymers that have a glass transition temperature (Tg)sufficiently above human body temperature which is approximately 37° C.,should be stiff or rigid upon implantation. Poly(L-lactide) (PLLA) isattractive as a stent material due to its relatively high strength and arigidity at human body temperature, about 37° C. As shown in Table 1,PLLA has high strength and tensile modulus compared to otherbiodegradable polymers. Since it has a glass transition temperature wellabove human body temperature, it remains stiff and rigid at human bodytemperature. This property facilitates the ability of a PLLA stentscaffolding to maintain a lumen at or near a deployed diameter withoutsignificant recoil (e.g., less than 10%).

Other rigid bioresorbable polymers include poly(D-lactide) (PDLA),polyglycolide (PGA), and poly(L-lactide-co-glycolide) (PLGA). The PLGAinclude those having a mole % of (LA:GA) of 85:15 (or a range of 82:18to 88:12), 95:5 (or a range of 93:7 to 97:3), or commercially availablePLGA products identified being 85:15 or 95:5 PLGA. Rigid polymers mayrefer to polymers that have a Tg higher than human body temperature orwithin 5 deg C. of human body temperature.

TABLE 1 Comparison of properties of bioressorbable polymers. TensileTensile Elongation Tm Tg Strength Modulus at break Absorption (° C.) (°C.) (MPa) (MPa) (%) Rate PLLA 175  65 28-50 1200-2700  6 1.5-5 yearsP4HB  60 −51 50  70 1000  8-52 weeks PCL  57 −62 16 400 80 2 years PDO 110¹  −10¹    1.5^(1,2)   30²  35³ 6-12¹ 6² PGA 225  35 70 6900  <3 6weeks DL-PLA Amorphous 50-53 16 400 80 2 years P3HB 180  1 36 2500   3 2years PLLA (poly(L-lactide); P4HB (poly-4-hyroxybutyrate); PCL(polycaprolactone); PGA (polyglycolide); DL-PLA (poly(DL-lactide); P3HB(poly-3-hydroxybutyrate); PDO (p-polydioxanone) All except PDO, Martinet al, Biochemical Engineering 16 (2003) 97-105. ¹Medical Plastics andBiomaterials Magazine, March 1998. ²Medical Device Manufacturing &Technology 2005. ³The Biomedical Engineering Handbook, Joseph D.Bronzino, Ed. CRC Press in Cooperation with IEEE Press, Boca Raton, FL,1995.

The mechanical properties such as strength and stiffness of asemi-crystalline polymer are highly dependent on and vary with thedegree of crystallinity. As a consequence, the radial strength andstiffness of scaffold made from a bioresorbable semi-crystalline polymeris likewise dependent on the crystallinity. In general, the strength andstiffness (and radial strength and radial stiffness) increase with anincrease in crystallinity.

The crystallinity of a semi-crystalline polymer construct variessignificantly with different processing methods used in its manufacture,where extrusion, injection molding, thermoforming and fiber spinning areamong the methods utilized for processing semi-crystalline polymers. Thekey to altering the mechanical properties is by fine tuning the degreeof crystallinity, and the crystal structure to obtain the most desirableproperties, which may include fracture toughness, flexibility andmechanical strength, which results in desirable scaffold properties,i.e., reduced scaffold fracture and high radial strength.

The fabrication process of a bioresorbable scaffold can include thefollowing steps:

(1) forming a polymeric tube using extrusion or injection molding,

(2) processing step to increase strength of the formed tube,

(3) forming a stent scaffolding from the processed tube by lasermachining a stent pattern in the tube from step (1) or (2) with lasercutting,

(4) optionally forming a therapeutic coating over the scaffolding,

(5) crimping the stent over a delivery balloon, and

(6) sterilization with election-beam (E-Beam) radiation.

The polymer tube may have walls that are free of any gaps or holes.Detailed discussion of the manufacturing process of a bioabsorbablestent can be found elsewhere, e.g., U.S. Patent Publication No.20070283552, which is incorporated by reference herein.

In an extrusion step, a polymer is processed in an extruder above themelting temperature of the polymer and then conveyed through a die toform a polymer tube. In step (2) above, the extruded tube may besubjected to a process that modifies the crystallinity of the extrudedtube to increase the radial strength of the tube, and thus, the finishedscaffold. The increase in strength reduces the thickness of the strutsrequired to support a lumen with the scaffold when expanded at animplant site. In exemplary embodiments, the strut thickness can be100-250 microns, or more narrowly, 120-180, 130-170, or 140-160 microns,160 to 200 microns, or 180 to 220 microns.

Previously disclosed processing methods to increase strength includeprocessing methods that modify crystallinity, crystal structure, andmorphology. These methods include annealing the polymer tube, typicallyat a temperature between Tg and Tm of the polymer. A scaffold may thenbe formed from the annealed polymer tube.

Other methods of increasing strength include radially expanding the tubefrom an original to an expanded diameter, also typically at atemperature between Tg and Tm. Although crystallinity may be induced dueto the temperature, the crystallinity in this method is inducedprimarily through strain-induced crystallization. A scaffold may then beformed from the tube at the expanded diameter.

Embodiments of the present invention include a scaffold fabricationprocess that includes a step of exposing a polymer construct to a liquidfor a period of time that modifies the crystallinity of thebioresorbable polymer which increases its strength. The liquidpenetrates or is absorbed into the bioresorbable polymer and induces orincreases the crystallinity of the bioresorbable polymer. The polymerconstruct is an intermediate in a scaffold fabrication process, forexample, a polymer tube.

The method can include obtaining or making a polymer tube and exposingthe polymer tube to a liquid penetrant for a period of time. Thecrystallinity of the polymer tube is induced or increased during thisexposure. A scaffold may be the fabricated from the exposed tube throughlaser machining a pattern into the tube. A bioresorbable scaffold isfabricated scaffold from the exposed tube. The resulting scaffold hasincreased strength due to the increased crystallinity. Some or all ofthe penetrant can be removed from the exposed tube prior to fabricatingthe scaffold.

The exposure to the penetrant can be performed at ambient temperaturewhich is at or about 25 deg C., or 20 to 30 deg C. Additionally, theexposure can be performed at a temperature greater than ambient, forexample, at or about 37 deg C. or 37 to 45 deg C. Exposure at aparticular temperature can be achieved by exposing a sample to apenetrant that is at a particular temperature.

In some embodiments, the exposed polymer tube is radially expanded to anexpanded diameter and a scaffold can be fabricated from the tube at theexpanded diameter. The tube can be radially expanded prior to removal ofthe penetrant from the tube. In this case, the penetrant may plasticizethe polymer enabling radial expansion at a temperature below the dry Tgof the polymer. For example, the tube may be expanded at about ambienttemperature, 25 deg C., or 20 to 30 deg C. Alternatively, some or all ofthe penetrant can be removed from the polymer tube prior to the radialexpansion. In this case where all the penetrant is removed, the tube maybe expanded at a temperature between Tg and Tm of the dried exposedtube.

In other embodiments, a scaffold is fabricated from the exposed tubewith no radial expansion of the exposed tube.

The liquid or penetrant is defined as a fluid that is capable ofpenetrating or being absorbed into a polymer into the bulk of thepolymer and further capable of modifying crystallinity of the polymerupon the penetration or absorption. The penetrant may penetrate thepolymer through one or more molecular diffusion mechanisms. For example,the diffusion of penetrants in the polymer can be Fickian (case I) ornon-Fickian The penetrant is further capable of penetrating or theswelling the polymer without dissolving the polymer.

The induced crystallization may be referred to as solvent-inducedcrystallization. Solvent-induced crystallization is a complex phenomenoninvolving the coupled processes of diffusion, swelling, andcrystallization. Several variables can affect the rate and/or extent ofeach process and the development of crystalline morphology includinginitial crystallinity/orientation, molecular weight distribution, andsolvent chemistry. Without being limited by theory, a solvent orpenetrant diffuses into a polymer and induces crystallization becausethe solvent lowers the crystallization temperature of the polymer. Inparticular, absorption of a penetrant by the polymer tends to decreasethe Tg of the polymer. As a result of a decrease of the Tg, thetemperature at which polymer chains may have sufficient mobility toalign and crystallize decrease.

Suitable penetrants depend on the type of polymer and its crystallinemorphology since different penetrants will have a different effect onthe given polymer. Representative penetrants for PLLA and other polymersinclude, but are not limited to, methanol, ethanol, isopropyl alcohol,acetone, and chloroform.

Representative methods of exposing the tube can include, but are notlimited to, immersing and soaking the tube in the penetrant, sprayingthe tube with the penetrant, and applying the penetrant with anapplicator such as a brush.

The polymer tube is exposed a polymer for a period of time which can be1 to 4 hr, 4 hr to 24hr or 1 day, 1 to 4 days, 4 days to 1 week, and 1week to 4 weeks. The time of exposure can be determined or dictated bycrystallinity modification and/or mechanical property modificationprovided by a given penetrant in a given time frame. The amount ofpenetrant absorbed (% uptake of penetrant), the kinetics or rate ofuptake of penetrant, and the magnitude and time for saturation of thepolymer depend on the given penetrant-polymer combination.

In general, it is desired to achieve particular crystallinitymodification and mechanical property modification in the shortest time.This makes a manufacturing process more efficient.

The mechanical properties of the bioresorbable polymer can be modifiedby the exposure to the penetrant, while still absorbed in the polymer.The modulus of a soaked material may decrease by 10 to 20%, 20 to 30%,30 to 40%, by at least 30%, or by at least 40%. Depending on thepenetrant and polymer combination, the drip can occur in 1 to 2 hr, 2 to24 hr, 1 to 8 days, 6 to 8 days, or 8 to 10 days. The elongation atbreak of a soaked material may increase by 40 to 50%, 50 to 70%, 70 to100%, 100 to 150%, 150 to 200%, 200 to 250%, by at least 100%, or by atleast 200%. Depending on the penetrant and polymer combination, theincrease can occur in 1 to 2 hr, 2 to 24 hr, 1 to 8 days, 6 to 8 days,or 8 to 10 days.

The inventors have found for PLLA surprising and unexpected differencesamong solvents in the % uptake, kinetics of the uptake, saturationuptake, effect on mechanical properties in the dry and wet states,penetration mechanisms, effect glass transition properties, and degreeof crystallinity induced.

The % uptake of penetrant in the tube is defined as:

$\frac{{{exposed}\mspace{14mu} {sample}\mspace{14mu} {weight}} - {{initial}\mspace{14mu} {sample}\mspace{14mu} {weight}}}{{initial}\mspace{14mu} {sample}\mspace{14mu} {weight}}$

where a sample can be a polymer tube. The % uptake of penetrant of canbe 1 to 6%, 1 to 10%, 1 to 2%, 1 to 4%, 2 to 4%, or 2 to 6%. The polymersample may be exposed for the period of time to reach a saturation %uptake, which is the maximum % uptake for a particular polymer sample.The polymer may also be exposed for a period of time to reach a % uptakethat is below a saturation level.

The initial crystallinity of tube can be amorphous or substantiallyamorphous. For example, the initial crystallinity can be less than 5%;less than 1%, less than 2%, or less than 5%. The initial crystallinitycan also be 1 to 5%, 1 to 2%, or 2 to 5%. The tube can also besemi-crystalline prior to exposure and have an initial crystallinity of10 to 55%, 10 to 20%, 20 to 30%, 30 to 40%, or 40 to 55%. Thesemi-crystalline tube can be a polymer tube has been subjected toanother type of crystallinity modification process, such as annealing orradial expansion.

In some embodiments, a scaffold including absorbed penetrant is crimpedover a delivery balloon from an as-fabricated diameter to a reducedcrimped diameter. The concentration of penetrant can be as describedabove. As shown in Table 4, the absorbed penetrant can decrease themodulus and increase the elongation of break of the bioresorbablepolymer of a tube. Therefore, fracture during the crimping process canbe reduced or eliminated. The scaffold may be at ambient temperatureduring crimping. After crimping, the penetrant can be removed from thescaffold through evaporation at ambient temperature or by heating thescaffold to a temperature above ambient temperature, for example, 30 to45 deg C.

In some embodiments, a scaffold can be made from a tube that includes nopenetrant. The scaffold may then be exposed to a penetrant in a mannerdisclosed above for a tube. The scaffold can then be crimped asdescribed.

EXAMPLES

A study was conducted to investigate the modification of PLLA constructsthrough exposure to various types of penetrants, in order to alter andtailor the mechanical properties to enhance the product quality in amanufacturing process. The penetrants studied included water, ethanoland methanol.

The following were studied:

-   -   penetrant sorption, desorption, and kinetics were studied        gravimetrically;    -   thermal analysis using differential scanning calorimetry (DSC)        which was used to study the change in fictive temperature        (glassy structure), glass transition temperature, cold        crystallization temperature;    -   crystal structure using wide angle x-ray scattering; and    -   mechanical testing.

Studies were performed on amorphous and semi-crystalline PLLA samples.The amorphous PLLA samples were extruded tubes with an outer diameter(OD) of 4 mm and a wall thickness of 1.5 mm. The semi-crystalline PLLAsamples were expanded extruded tubes with an OD of 9 mm and wallthickness of 200 microns.

Penetrant Sorption, Desorption and Kinetics

Prior to the sorption studies, the materials were dried in vacuum for 2weeks to obtain completely dried samples in order to make sure that themeasured change of weight is due to sorption of penetrant and notmoisture from the air. Three different penetrants were used for thesorption studies: water, ethanol and methanol. The sorption wasconducted by soaking the samples at 37° C. and measuring the weightchange gravimetrically with Precisa high precision balance model XR205SM-DR. The uptake was measured in percentage, calculated by dividingthe mass increase with the initial mass after drying the samples invacuum and before the soaking

Desorption of the samples were conducted in an auto-dessicator fromSecador with blue gel dessicant placed inside, furthermore, the box wasequipped with a ventilation engine to provide the box with fresh air andkeep it free from chemicals, like alcohol in this case.

Three samples were used for each experiment. In addition, the sampleswere cut and prepared in a way that enables the use of one-dimensionaldiffusion equation, and for sorption kinetics obeying Fickian diffusion,following expression can be used to calculate the diffusion constant D:

$D = \frac{0.049\; l^{2}}{t_{1/2}}$

Thermal Analysis

Thermal analyses were characterized by using differential scanningcalorimeter (DSC). The DSC studies were conducted by soaking the PLLAsamples for various times in the three different penetrants water,ethanol and methanol. The soaking times were 1, 5, 25, 72 h, 1 week and4 weeks. The data was obtained and performed with a Mettler Toledo DSC 1differential scanning calorimeter using Mettler Toledo STARe V9.2software. This was conducted in order to measure the change of fictivetemperature, T_(f), and change of crystallinity in the samples as afunction of soaking and aging time. The samples were characterized inboth wet and dry state. In the wet state the DSC was conductedimmediately after soaking without removing penetrant, while in the drystate, the samples were dried in vacuum oven 3-20 days, depending onpenetrant and soaking time, also with help from desorption curves, tomake sure the samples were completely dry.

The amorphous PLLA samples were cut along the axial direction of thetubes, while semi-crystalline PLLA samples were cut in small pieces inorder to gain continuous contact with the bottom of the DSC cup toreduce noise. The samples size were about 15 mg per each, and a heatingrate of 10 K/min for the amorphous- and semi-crystalline PLLA were used.On both the amorphous and semi-crystalline PLLA samples the DSC cups wassealed and isolated without ventilation holes.

DSC data and thermograms were used to calculate the fictive temperature,T_(f), (glassy state) of the polymer.

Wide-Angle X-ray Diffraction (WAXD)

WAXD analysis was performed on an X'Pert PRO PANalytical (Cu Kαradiation) under a voltage of 45 kV and a current of 35 mA. Dataevaluation was performed on X'Pert High Score Plus. The 2θ-angle was inan angular range of 2° to 60°. Amorphous and semi-crystalline PLLAsamples were analyzed at the end of the soaking experiments.

Tensile Testing

Tensile testing was conducted with an Instron 5944 Universal Testingmachine, in order to see the change of mechanical properties as afunction of penetrant and soaking time. The Instron was equipped with a50 N load cell. The samplings were performed with a pulling rate at 100mm/min, and distances of 10 mm between the grips were used. Due to thetube shaped geometry the samples were not formed as dumb-bells; insteadthey were linearly marked with straight lines approximately 2 mm withruler followed by cutting them in thin stripes along the axialdirection.

Results for Penetrant Sorption, Desorption, and Kinetics Water Sorption,Desorption and Kinetics

FIG. 2 shows the water sorption of amorphous PLLA and semi-crystallinePLLA samples soaked in water as a function of the square root of time(h)^(1/2). Both the amorphous and semi-crystalline PLLA obeys Fickian(case I) diffusion behavior. In both cases, the initial part of thecurve is linear, and when sorption saturation is reached the curvelevels off and a constant mass increase is obtained. The amorphous PLLAsamples reached saturation in about 2 days and the water uptakes wereapproximately 0.1%. The semi-crystalline PLLA samples reached saturationmuch faster, and were fully saturated within one day. However, the wateruptakes were approximately 0.06% and lower for the semi-crystallinesamples than the amorphous PLLA samples. The sorption values ofamorphous and semi-crystalline PLLA correlates with values obtained byisothermal sorption at 40° C. and 90% relative humidity (RH), R. A.Cairncross, S. Ramaswamy, R. O'Connor: International Polymer Processing(2007), 22, (1), 33-37.

An explanation for the lower water uptake of the semi-crystalline PLLAcould be due to the degree of crystallinity in the samples. It isbelieved that the sorption mechanism is diffusion into the materialthrough the amorphous phase and not through the semi-crystalline phase.If this is the case, this means that when sorption of an amorphouspolymer has reached equilibrium, it is the highest sorption possiblethat this material can reach. However, for a semi-crystalline polymerthe highest sorption possible is the same as the amorphous polymer lessthe degree of crystallinity in the polymer. In the present case thesemi-crystalline polymer has a crystallinity of approximately 40%,meaning that the water uptake of the semi-crystalline PLLA samples canreach 60% water sorption of the amorphous PLLA samples.

FIG. 3 shows the desorption curves of the water soaked PLLA samples.Desorption kinetics of the samples correlates to the sorption kineticsof the amorphous and semi-crystalline PLLA samples, meaning that fastsorption also results in fast desorption as in the case ofsemi-crystalline PLLA samples, whereas the amorphous PLLA samples thatshowed a slower uptake also showed a slower desorption.

Methanol Sorption and Kinetics

FIG. 4 shows methanol sorption curves of amorphous PLLA samples. Thecurve has a two-stage characteristic diffusion with different sorptionkinetics. It has a fast initial methanol uptake, of 1.5%, within thefirst two hours of methanol soaking, followed by a slow and linearpenetrant sorption of methanol that did not reach saturation within 4 or5 weeks. The slow methanol uptake of amorphous PLLA samples is somewhatunexpected compared to the methanol sorption of semi-crystalline PLLAsamples, also shown in FIG. 4. The curve has two-stage characteristicbehavior due to competing mechanisms between solvent inducedcrystallization and sorption uptake.

The semi-crystalline samples have a fast linear initial uptake thatreaches saturation, at or about 6%, within at, or about 25 h. Thediffusion is similar to the Fickian (case I) diffusion. However, thesorption does not reach constant uptake but rather decreases, almostdown to 5%, with additional soaking time.

Possible explanations for the decrease in weight change of methanolsorption can be that low molecular weight chains inside the bulkmaterial are slowly being filtered out from the material. Anotherhypothesis is that the decrease in weight change is due to solventinduced crystallization [S Mitsuhiro, T Naozumi, I Yusuke: Polymer(2007), 48, (9), 2768-2777], which was tested with DSC studies discussedherein. The latter hypothesis of induced crystallization can also be thereason to the slow uptake of methanol in the amorphous PLLA samples.

Furthermore, since the methanol sorption of amorphous PLLA is slowalready after 2 h of soaking, it also means that induced crystallizationoccurs very fast. This indicates that methanol sorption of the amorphousPLLA samples has two mechanisms that counteract each other. The methanolsorption in semi-crystalline PLLA samples is fast. In addition, it isbelieved that lower methanol uptake is obtained from the amorphous PLLAsamples than the semi-crystalline samples as a consequence to theinduced crystallization.

FIG. 5 shows the desorption of the methanol soaked PLLA samples. Theamorphous PLLA samples did not reach the initial weight, prior tosorption experiments, within the timeframe of the desorptionexperiments. The desorption curve exhibits variation in desorptionkinetics, being slightly steeper the first 25 hours and slowlyflattening out during rest of the desorption experiment. Desorption ofthe semi-crystalline PLLA samples appears to correlate with the sorptionof methanol uptake, a fast uptake also results in a fast desorption.Furthermore, desorption of the semi-crystalline PLLA samples soaked inmethanol did reach a weight below the initial weight of the samplesprior to the sorption experiments. This supports the theory that lowmolecular weight chains inside the bulk material were slowly beingfiltered out from the material, as described above.

Ethanol Sorption and Kinetics

FIG. 6 shows the ethanol sorption of amorphous and semi-crystalline PLLAsamples. Ethanol sorption of the amorphous PLLA samples has a linearuptake in the beginning of the curve, and when sorption saturation isreached at about 6% in about 4 days, the curve levels off and a constantpenetrant uptake is obtained; showing that ethanol sorption of amorphousPLLA samples also obeys Fickian (case I) diffusion behavior. FIG. 6 alsoshows that the ethanol uptake of 6% which is much higher than the watersorption of the amorphous PLLA.

The sorption curve of semi-crystalline PLLA samples soaked in ethanolhas a slight S-shaped form indicating a non-Fickian or anomalousdiffusion behavior. The saturation uptake of 5% was reaches in about 8days. This behavior tends to occur when the diffusion and relaxationrates are comparable, and it is associated with the restricted rates atwhich the polymer structure may change in response to the sorption ofpenetrant molecules. In addition, the ethanol sorption ofsemi-crystalline samples also has a higher penetrant uptake, 5%, thansemi-crystalline PLLA samples soaked in water.

Ethanol uptake of the amorphous PLLA samples was also higher than thesemi-crystalline samples, however, the difference was not as high as 40%more uptake for the amorphous samples. The difference between amorphousPLLA and semi-crystalline PLLA is less than 40% after a certain time ofsoaking, which results in a lower difference in uptake between the PLLAsamples. A hypothesis for the lower difference of ethanol uptake betweenthe amorphous PLLA compared to the semi-crystalline PLLA is also that itis due to solvent induced crystallization, which was tested with DSC anddiscussed herein.

Furthermore, soaking time to reach sorption saturation was much longerfor ethanol sorption than water sorption. The amorphous PLLA samplestook about 4 days to reach saturation of 6%, while it took about a weekfor the semi-crystalline samples to reach saturation. A possibleexplanation for the longer sorption saturation time is that the amountof ethanol sorption is much higher than the water sorption. It isbelieved that the difference in uptake is due to the differenthydrophilicity between water and ethanol or affinity and solubility withPLLA, since both water and ethanol are hydrophilic.

FIG. 8 shows an affinity test of penetrant and semi-crystalline PLLA.The image shows how the water forms a droplet on the material indicatinghydrophobic characteristic of the PLLA. However, ethanol and methanol donot form a droplet showing that those two solvents have a high affinitywith the material. Due to the high affinity, the ethanol and methanolare able to penetrate into the material thus leading to rather highsorption of approximately 6%. Water on the other hand does not seem tobe absorbed or penetrate the material, thus leading to the low and fastuptake of water soaked samples.

FIG. 7 shows desorption of the ethanol soaked PLLA samples. As can beseen on the desorption curves, none of the amorphous or semi-crystallinePLLA samples reached the initial weight within the time frame of thedesorption experiments. The desorption of ethanol soaked samples did notappear to correlate with the sorption uptake as was shown in the case ofwater, desorption of ethanol seemed to be slower than the sorptionuptake. A possible reason is the stronger affinity between ethanol andPLLA, which may require stronger desorption mechanism than the way theexperiments were conducted. Conducting desorption in vacuum may havedried out the samples faster and completely by reaching the initialweight.

Furthermore, another possible explanation to the slow desorption lieswithin the crystal structure of the PLLA. Depending on thecrystallization conditions, it is possible that a polymorphic crystalstructure has been obtained, containing α and α′ crystals. It has beenreported that the α′ is less stable and is characterized by a slightlylarger lattice dimension and looser PLLA chain arrangements. [M. L DiLorenzo, et al., Crystal polymorphism of poly(L-lactic acid) and it'sinfluence on thermal properties, Thermochim.Acta (2011), doi:0.1016/j.tca.2010.12.027] It may be possible that the larger and looserα′ crystal structure encapsulates the methanol and traps the moleculesinside the lattice, thus resulting in slower desorption of ethanol.

Thermal Analyses DSC Characterization of Amorphous PLLA Samples Soakedin Water, Ethanol and Methanol

The change of fictive temperature of all the wet PLLA samples ispresented in Table 2, while fictive temperatures of the dried samplesare presented in Table 3.

TABLE 2 Calculated fictive temperature of amorphous PLLA and semi-crystalline PLLA samples at wet state after soaking. Soaking time: Nosoak- 1 5 25 72 1 4 ing h h h h week weeks Amorphous PLLA Water samples58.0 56.9 53.4 50.1 45.7 44.6 41.7 Ethanol Samples 58.0 54.6 53.8 53.449.8 46.0 40.8 Methanol Samples 58.0 54.7 45.8 33.0 34.7 34.1 34.8Semi-cryst. PLLA Water samples 75.6 70.8 69.1 69.5 72.5 71.3 66.3Ethanol Samples 75.6 69.2 66.2 51.7 48.5 43.3 45.7 Methanol Samples 75.667.5 63.99 47.8 37.9 36.9 37.9

TABLE 3 Calculated fictive temperature of dried amorphous PLLA andsemi-crystalline PLLA samples. Soaking time: No soak- 1 5 25 7 1 4 ing hh h 2 h week weeks Amorphous PLLA Water samples 58.0 55.20 58.13 52.1351.13 51.12 49.39 Ethanol Samples 58.0 55.84 55.76 55.26 52.42 52.2847.23 Methanol Samples 58.0 54.51 50.08 47.20 54.04 59.36 58.10Semi-cryst. PLLA Water samples 75.6 68.97 69.19 71.30 69.59 72.03 69.19Ethanol Samples 75.6 71.11 68.34 64.88 67.13 62.38 62.40 MethanolSamples 75.6 69.56 69.04 64.38 72.45 72.64 73.77

FIG. 9 shows DSC thermograms of water soaked amorphous PLLA samples. Thereference sample in the bottom, followed by samples that have beensoaked 1 day (middle), and 4 weeks (top). FIG. 9 shows that thehysteresis peak is shifted to the left with increased soaking time, asshown with the arrow, starting at 68.5° C. and ending at 63.5° C. after4 weeks soaking A consequence of this shift is a depressed fictivetemperature which changes the glassy structure of the polymer.Furthermore, a shift of the cold crystallization peak also occurs,decreasing from 106° C. down to 100° C. after 4 weeks of soaking. Thefictive temperature of wet state, water soaked amorphous PLLA samples,was lower than the dried samples that been soaked more than 25 hours.These results indicate that water sorption does lower the T_(f) ofamorphous PLLA. Furthermore, by comparing the T_(f) values obtained byaging the samples at 40° C. [16] in dried environment, presented intable 3, the results also indicate that PLLA ages faster in wetenvironment than in dry environment.

FIG. 10 shows DSC thermograms of ethanol soaked amorphous PLLA samples.The reference sample is at the bottom, followed by samples that havebeen soaked 3 days (middle), and 4 weeks (top), respectively. Thethermograms show a major difference in the ethanol soaked samplescompared to the water soaked samples. A transition is shown to developin the region around 37° C., indicating a double Tg. After 4 weeks ofsoaking the double Tg has disappeared into one Tg, resulting in a widerange of the Tg. The hysteresis peak is also shifted to left, as thewater soaked samples, and simultaneously the cold crystallization peakis diminished with soaking time and is almost erased after 4 weeks ofsoaking, as shown by the top-most curve. This indicates that the degreeof crystallinity in the samples increases with soaking time in ethanolsince; the degree of crystallinity in the samples is calculated bysubtracting the cold crystallization peak with the crystallizationmelting peak.

For non-treated samples, references, the degree of crystallinity is1-2%. After 4 weeks of soaking in ethanol, the degree of crystallinityis 58%. Some increase of heat flow in the thermograms is due toevaporation heat of the ethanol penetrant, however, the ethanol sorptioncurve of amorphous PLLA samples in FIG. 6, which showed that sorptionsaturation, is reached within 1 week of sorption in ethanol. Thisindicates no increase of ethanol uptake occurs when saturation isreached for the ethanol soaked samples, however, the thermograms in FIG.10 showed a gradual decrease in cold crystallization peak even after 1week, meaning that an increased and induced crystallization is obtaineddue to ethanol sorption of amorphous PLLA samples. T_(f) of the ethanolsoaked samples is lower for all the wet amorphous samples compared todried samples, which shows the plasticizing effect of ethanol on PLLA.

FIG. 11 shows the DSC thermograms of methanol soaked amorphous PLLAsamples. The curve of the reference sample is at the bottom, followed bysamples that have been soaked 1 day (middle), and 4 weeks (top)respectively. The characteristic thermograms of methanol soaked samplesare even more different compared to the thermograms on FIGS. 9 and 10.It can be seen on FIG. 11 that after 1 day of soaking the thermogram ofmethanol soaked samples, middle curve, show similar character to the 4weeks of soaking in ethanol in FIG. 10 (topmost curve). The degree ofcrystallinity of the methanol soaked sample is 62%, which is comparableto the 58% crystallinity, obtained from 4 weeks of ethanol soakedsamples.

Furthermore, the amorphous PLLA samples do not show any coldcrystallization at all after 3 days of soaking, and the trend remainseven after 4 weeks of soaking time. In addition, due to the erased coldcrystallization peak, the fictive temperature is rapidly depressed from58° C. down to 34° C. within 1-2 days of soaking in methanol at 37° C.,as shown in Table 2.

FIG. 12 shows DSC thermograms of the dried methanol soaked amorphousPLLA samples. The dried methanol soaked samples of amorphous PLLAcharacterized with DSC showed that after 25 hours of soaking the coldcrystallization peak has disappeared when the samples have been driedout. This indicates that an irreversible change in morphology hasoccurred, transitioning the samples from amorphous to a semi-crystallinestructure. Without the cold crystallization peak of amorphous PLLA thethermograms look somewhat similar to the thermograms of semi-crystallinePLLA, shown in FIG. 13.

However, the most remarkable difference between methanol inducedcrystallization shown in FIG. 12, and the semi-crystalline PLLA DSCthermograms in FIG. 13, is that there is two semi-crystalline PLLAstructures with different T_(g). The T_(g) from methanol inducedcrystallization of the isotropic amorphous PLLA samples areapproximately 58° C., the same as the initial fictive temperature. Whilethe highly oriented semi-crystalline PLLA samples have a T_(g) of 75° C.The difference in chain orientation obtained by the two processingmethods shows up as different Tg's and means it is possible to obtainsemi-crystalline PLLA with the same T_(g) as amorphous PLLA by methanolinduced crystallization. This more isotropic PLLA should have morestable shelf-life properties and most likely better fracture fatigueproperties.

DSC Characterization of Semi-Crystalline PLLA Samples Soaked in Water,Ethanol and Methanol

FIGS. 13, 14, and 15 show DSC thermograms of water-, ethanol-, andmethanol-soaked semi-crystalline PLLA samples, respectively. In FIGS. 13and 14, the thermograms show the reference sample in the bottom,followed by average value of samples that have been soaked 3 days(middle) and 4 weeks (top), respectively. In FIG. 15, the referencesample in the bottom, followed by samples that have been soaked 1 day, 3days, 1 week, and 4 weeks. The change of fictive temperature from thesemi-crystalline PLLA samples is presented in Table 2.

The water soaked samples of semi-crystalline PLLA did not show anychange in degree of crystallinity. However, a small change of thefictive temperature was measured, presented in Table 2, which shows thata fast initial drop of fictive temperature occur after one hour ofsoaking; depressing the fictive temperature from 75.6° C. down to 70.8°C. The fictive temperature then remains around 69-71° C., independent ofsoaking time. However, after 4 weeks of soaking the fictive temperatureis depressed further down to 66° C.

The change of fictive temperature for semi-crystalline PLLA samplessoaked in ethanol and methanol is also presented in Table 2. Thermogramsfor the ethanol (FIG. 14) and methanol (FIG. 15) soaked samples showeddifferent characteristic behavior compared to the water soaked samples,FIG. 13, in which all the thermogram curves look similar to each other.The fictive temperature in both ethanol and methanol soaked samples weremuch more depressed than the water soaked samples, having a fictivetemperature around 45° C. and 37° C., respectively, after 4 weeks ofsoaking time.

Furthermore, the thermograms of the semi-crystalline samples soaked inethanol and methanol also indicates an induced crystallization, havingan additional melting peak that increases with soaking time. This ismore distinguishable for the methanol soaked samples, FIG. 15. Asmentioned before, there is an increase in heat flow contributed by theheat of evaporation of the ethanol and methanol penetrants. The relativecontribution of the increase in heat flow from the heat of evaporationand melting of crystals is not shown by the data. However, by looking atthe sorption curve for semi-crystalline PLLA samples soaked in methanol,FIG. 5, it can be seen that saturation is reach within 25 h indicatingthat no increase of methanol uptake occurs. Instead a slight decrease ofthe methanol sorption uptake can be seen. It is believed that this dueto induced crystallization, which is shown by the DSC thermograms. Sincethere is no additional uptake of methanol after 1 day of soaking, thisindicates that there should not be any more contribution from heat ofevaporation for samples soaked 3 days and longer. However, it is clearlyseen on thermograms for the methanol soaked samples, FIG. 15, that theheat flow and melting peak increase with soaking time, indicating thatinduced crystallization does occur for methanol soaked samples. Althoughthe data for induced crystallization is not as evident for ethanolsoaked samples, there are reasons to believe that it does occur, sinceit occurs for amorphous PLLA soaked in ethanol.

DSC characterization of dried semi-crystalline samples soaked in water,ethanol, methanol did not show any major change in crystallinity.However the change in T_(f) of the dried samples, presented in Table 3,shows that the T_(f) of the water soaked samples rapidly decreases to69° C., already after 1 hour of soaking, and is kept there ±1° C.independent of the soaking time. Dried ethanol soaked samples do show asteady decrease of T_(f), being kept around 62° C. after one week ofethanol soaking

However, looking back at FIG. 7, the desorption curve of ethanol soakedsamples, it showed the difficulty for ethanol to desorb. Consideringthat the wet samples had a much lower T_(f) it is possible that thesamples were not completely dry at the moment of DSC characterization.The dried methanol soaked samples showed a u-shaped change of T_(f),indicating that it decreased the first 25 hours of soaking from 75.6° C.to 64.4° C. and increased to 72° C. after 72 hours of soaking Itremained at 72±1° C. even after 4 weeks of soaking, indicating adecrease in T_(f) of only 2° C. after 4 weeks of aging.

Referring to FIG. 12, the amorphous PLLA undergoes an irreversiblechange. The same change may occur in the amorphous phase on thesemi-crystalline samples, which results in a polymorphic crystalstructure and consequently results in a very low change of T_(f) at drystate of the methanol soaked samples, compared to water and ethanolsoaking.

X-Ray Measurements

WAXD patterns of the amorphous and semi-crystalline PLLA samples areshown in FIGS. 16 and 17, respectively. FIG. 16 shows the WAXD patternof the dry amorphous sample without soaking at the bottom of the figure.The WAXD pattern of samples soaked in water is second from the bottom.These two samples show an amorphous halo, indicating there is no changein crystallinity when soaking the samples in water for 4 weeks.

The WAXD patterns of the ethanol and methanol soaked samples are secondfrom the top and the top-most, respectively on the figure. For both ofthese patterns, two peaks at approximately 16.7° and 19.1°, haveappeared after soaking the samples for 4 weeks. The peaks at those 2θvalues corresponds to reflection of (2 0 0)/(1 1 0) and (2 0 3) planesin an α-crystallized orthorhombic unit cell [17].

FIG. 17 shows the WAXD pattern of dry semi-crystalline sample withoutsoaking at the bottom of the figure with peaks at approximately 17.3°,19.2° and 24.3°. A shift of 2θ values of crystals is possible anddepends on crystallization temperature, T_(c). The first two peaksindicates α-crystals with a shift on the (2 0 0)/(1 1 0) planes from16.7° to 17.3 ° and from 19.1° to 19.2° of the (2 0 3) plane. Theadditional peak, compared to FIG. 16, at 24.3° indicates a polymorphicstructure where α- and α′-crystals coexist [15]. The same kind of peaksis also shown in FIG. 17 on the water soaked samples, second from thebottom, as well as the two other peaks around 17° and 19°, indicatingthat no change in crystallinity has occurred from the water treatment.

For the ethanol soaked samples, the second from the top in FIG. 17, theWAXD patterns show higher intensity of the peaks around 17° α- andα′-crystals and 19° than the non- and water soaked samples. The higherintensity indicates an increase in the degree of crystallinity of thesample. Furthermore, whether the peak around 24.3° has disappeared ordiminished. Its disappearance indicates that the ethanol soaking mayhave transitioned the polymorphic crystal structure of α- andα′-crystals to pure α-crystalline structure. However, it is believedthat that such transition is unlikely to occur only due to ethanolsoaking and that such a difference may require thermal treatment toobtain such a transition. Furthermore, the slow desorption of ethanolshows that some kind of entrapment of ethanol molecules does occur.

The WAXD patterns of the methanol soaked samples, the top-most curve inFIG. 17, shows an extremely high increase of the intensity at 16.5°,which is a slight shift of the peak compared to the non-, water-, andethanol soaked samples. There are also additional peaks appearing at14.6°, 22.3° and 28.7° which corresponds to reflection of (0 1 0), (0 15) and (0 1 8) planes respectively. The peaks corresponds tocrystallization of PLLA between 105° C.≦T_(c)≦125° C., which also meansthat methanol soaking results in a polymorphic structure where α- andα′-crystals coexist [15].

Tensile Testing and Change of Mechanical Properties

The change of mechanical properties of semi-crystalline PLLA samples dueto soaking time and uptake of penetrant are presented in Table 4.Soaking time was 2 min, 70 min and 8 days in water, ethanol and methanolat 37° C., as well as samples dried for 4 days after 70 min and 8 daysof soaking of ethanol and methanol soaked samples.

TABLE 4 Mechanical testing data of semi-crystalline PLLA E-modulus inunits of GPa. 2 70 8 Solvent Reference min min Dried days Dried Water Emodulus 1.81 1.84 1.72 1.86 1.61 No data Elongation % 57 31 33 23 19 Nodata Ethanol E modulus 1.81 1.73 1.66 1.83 1.28 1.64 Elongation % 57 4564 19 97 117 Methanol E modulus 1..81 1.76 1.42 1.92 1.13 1.52Elongation % 57 56 101 18 180 33

The water soaked samples showed a slight change of mechanical propertieswith a decrease in E-modulus from 1.81-1.61 GPa after 8 days of soaking,and a lower strain at break resulting in a less flexible and stiffermaterial.

The ethanol soaked samples showed a decrease in E-modulus from 1.81 to1.71 GPa (about a 6% drop) and 1.81 to 1.28 GPa (about a 30% drop) after8 days of soaking, however, the strain at break increased from 45% up to97% (about 116% increase) indicating that a softer and more flexiblematerial is obtained, as a result of ethanol soaking This indicates thatethanol soaking has a plasticizing effect on the semi-crystalline PLLAsamples.

Methanol soaked samples showed similar results to the ethanol soakedsamples; however, the plasticizing effect was enhanced. Additionally,soaking in methanol appears to be more efficient due to similarproperties that can be obtained from shorter soaking time; 8 daysethanol soaking compared with 70 min methanol soaking The E-modulusdecreased from 1.81 to 1.42 GPa in 70 min (about 21% drop) and to 1.13GPa (about 38% drop) in 8 days of soaking The elongation increased from57 to 101% (about 77% increase) in 70 min and to 180 in 8 days (about a216% increase). This shorter time is probably due to faster uptake ofmethanol than ethanol in the material.

However, both ethanol and methanol sorption in semi-crystalline PLLAreached saturation after 8 days of soaking, as shown in FIGS. 7 and 5.Yet methanol soaked samples show a much more flexible property than theethanol soaked samples. This is further evidence of methanol as a muchmore efficient plasticizer than ethanol for semi-crystalline PLLA.

Also shown in Table 4, 4 days of drying after the soaking at 70 min, theE-modulus increased for all samples, and was even higher than theinitial E-modulus before soaking Furthermore, all the samples had alsobecome stiffer. 4 days of drying after 8 days of soaking the ethanolsamples had an increased E-modulus compared to the wet state. However,the strain at break increased which is not expected, since it isexpected to become stiffer in dry state than wet state. Considering that4 days of drying is not sufficient to dry the ethanol soaked samples,this is still surprising results. 4 days of drying of the methanolsoaked samples showed that the samples had a higher E-modulus at drystate than wet state and had become stiffer.

The plasticizing effect of ethanol and methanol soaked samples showsthat they are efficient as solvents for physical modification ofsemi-crystalline PLLA. The reason that water does not show the sameplasticizing effect is probably due to insufficient penetration into thematerial. The water only adsorbs to the surface and is not able topenetrate into the bulk. Ethanol and methanol, on the other hand, areable to penetrate into the bulk material and as a result they work wellas plasticizers.

Summary of Results

Water sorption of amorphous and semi-crystalline PLLA samples obeyedFickian diffusion, with an uptake of 0.06 and 0.1%, respectively,saturation was reached within 25 h in both cases. Water sorption alsodepressed the amorphous and semi-crystalline PLLA. However, no change incrystallinity was obtained from water soaking.

Ethanol sorption of amorphous PLLA samples obeyed Fickian diffusion. DSCof ethanol soaked samples also showed induced crystallization as didmethanol soaked samples. The semi-crystalline samples showed anomalousnon-Fickian diffusion behavior. The ethanol uptake was about 6% foramorphous PLLA and the saturation time was about 4 days, while theethanol uptake for semi-crystalline PLLA was about 5% and took about 8days to reach saturation.

Methanol sorption of amorphous PLLA samples are similar to Fickiandiffusion. However, instead of constant uptake, a decrease in weight isobserved which may be due to low molecular weight fractions are leachingout or due to induced crystallinity which decreases the uptake ofmethanol penetrant. DSC showed that the fictive temperature wassignificantly and rapidly depressed down to 34° C. Furthermore, the coldcrystallization peak disappeared after 1-2 days of soaking resulting ininduced crystallization. Semi-crystalline samples showed two-stagediffusion due to two competing mechanism, penetrant uptake and inducedcrystallinity which were proved with DSC.

The penetrant uptake of ethanol and methanol was approximately 5-6% onthe semi-crystalline PLLA samples which is high compared to 0.1% uptakeof water. This is believed due different affinity between water, ethanoland methanol with the PLLA samples, which was shown to be much higherfor ethanol and methanol. This also indicates that ethanol and methanolare efficient penetrants and plasticizers, while water is not.

The mechanical testing showed the plasticizing effect of ethanol andmethanol, resulting in a much more flexible material, especially frommethanol soaking However, the E-modulus also decreased as theflexibility increased.

“Molecular weight refers to either number average molecular weight (Mn)or weight average molecular weight (Mw).

“Semi-crystalline polymer” refers to a polymer that has or can haveregions of crystalline molecular structure and amorphous regions. Thecrystalline regions may be referred to as crystallites or spheruliteswhich can be dispersed or embedded within amorphous regions.

The “fictive temperature” is defined as the temperature at which thenonequilibrium value of the macroscopic property would be theequilibrium one. A. Tool and C. G. Eichlin, J. Am. Ceram. Soc. 14, 276(1931). T_(f) acts as a map between a nonequilibrium glass and anequilibrium liquid. A glass at a temperature T₁ has the same structureas a super cooled liquid at temperature T_(f). The fictive temperatureswere calculated by using an intercept method: This method compares areachange vs temperature and the trendline between these two area changesgives us the T_(f). The two methods are illustrated on FIG. 18.

The “glass transition temperature,” Tg, is the temperature at which theamorphous domains of a polymer change from a brittle vitreous state to asolid deformable or ductile state at atmospheric pressure. In otherwords, the Tg corresponds to the temperature where the onset ofsegmental motion in the chains of the polymer occurs. When an amorphousor semi-crystalline polymer is exposed to an increasing temperature, thecoefficient of expansion and the heat capacity of the polymer bothincrease as the temperature is raised, indicating increased molecularmotion. As the temperature is increased, the heat capacity increases.The increasing heat capacity corresponds to an increase in heatdissipation through movement. Tg of a given polymer can be dependent onthe heating rate and can be influenced by the thermal history of thepolymer as well as its degree of crystallinity. Furthermore, thechemical structure of the polymer heavily influences the glasstransition by affecting mobility.

The Tg can be determined as the approximate midpoint of a temperaturerange over which the glass transition takes place. [ASTM D883-90]. Themost frequently used definition of Tg uses the energy release on heatingin differential scanning calorimetry (DSC). As used herein, the Tgrefers to a glass transition temperature as measured by differentialscanning calorimetry (DSC) at a 20° C./min heating rate.

“Stress” refers to force per unit area, as in the force acting through asmall area within a plane. Stress can be divided into components, normaland parallel to the plane, called normal stress and shear stress,respectively. Tensile stress, for example, is a normal component ofstress applied that leads to expansion (increase in length). Inaddition, compressive stress is a normal component of stress applied tomaterials resulting in their compaction (decrease in length). Stress mayresult in deformation of a material, which refers to a change in length.“Expansion” or “compression” may be defined as the increase or decreasein length of a sample of material when the sample is subjected tostress.

Elongation at break of a material is the percentage increase in lengththat occurs before a sample made of the material breaks under tension.

“Strain” refers to the amount of expansion or compression that occurs ina material at a given stress or load. Strain may be expressed as afraction or percentage of the original length, i.e., the change inlength divided by the original length. Strain, therefore, is positivefor expansion and negative for compression.

“Strength” refers to the maximum stress along an axis which a materialwill withstand prior to fracture. The ultimate strength is calculatedfrom the maximum load applied during the test divided by the originalcross-sectional area.

“Modulus” or “stiffness” may be defined as the ratio of a component ofstress or force per unit area applied to a material divided by thestrain along an axis of applied force that results from the appliedforce. The modulus typically is the initial slope of a stress—straincurve at low strain in the linear region. For example, a material hasboth a tensile and a compressive modulus.

The tensile stress on a material may be increased until it reaches a“tensile strength” which refers to the maximum tensile stress which amaterial will withstand prior to fracture. The ultimate tensile strengthis calculated from the maximum load applied during a test divided by theoriginal cross-sectional area. Similarly, “compressive strength” is thecapacity of a material to withstand axially directed pushing forces.When the limit of compressive strength is reached, a material iscrushed.

“Toughness” is the amount of energy absorbed prior to fracture, orequivalently, the amount of work required to fracture a material. Onemeasure of toughness is the area under a stress-strain curve from zerostrain to the strain at fracture. The units of toughness in this caseare in energy per unit volume of material. See, e.g., L. H. Van Vlack,“Elements of Materials Science and Engineering,” pp. 270-271,Addison-Wesley (Reading, Pa., 1989).

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1. (canceled)
 2. A method of fabricating a bioresorbable stent scaffoldcomprising: providing a tube made of a bioresorbable polymer; exposingthe tube to a solvent for a period of time, wherein the solvent isabsorbed into the bioresorbable polymer which increases a crystallinityof the bioresorbable polymer; and fabricating a scaffold having apattern of interconnected struts from the exposed tube, wherein thesolvent is methyl alcohol.
 3. The method of claim 2, wherein thebioresorbable polymer is selected from the group consisting ofpoly(L-lactide) (PLLA) and poly(L-lactide-co-glycolide).
 4. The methodof claim 2, wherein the provided tube has a crystallinity of less than5% and the crystallinity is increased to at least 40%.
 5. The method ofclaim 2, wherein the period of time of exposing the tube to the solventis comprised from 1 to 4 days.
 6. The method of claim 2, wherein thesolvent does not dissolve the bioresorbable polymer.
 7. The method ofclaim 1, further comprising removing the absorbed solvent prior tofabricating the scaffold.
 8. The method of claim 2, wherein a modulus ofthe bioresorbable polymer decreases by at least 30% in 1 to 8 days ofexposure.
 9. The method of claim 2, wherein an elongation at break ofthe bioresorbable polymer increases by at least 100% in 1 to 8 days ofexposure.
 10. The method of claim 2, wherein the exposed tube is notradially expanded prior to fabricating the scaffold.
 11. The method ofclaim 2, wherein the exposed tube is radially expanded prior tofabricating the scaffold.
 12. The method of claim 2, wherein thebioresorbable polymer is poly(L-lactide).
 13. The method of claim 2,further comprising: radially expanding the exposed tube comprising theabsorbed solvent from a first diameter to a second diameter.
 14. Themethod of claim 13, wherein the temperature of the exposed tube isbetween 20 and 30 deg C. during the radial expansion.
 15. The method ofclaim 2, further comprising: crimping the scaffold comprising absorbedsolvent from a first diameter to a reduced diameter over a deliveryballoon.
 16. The method of any of the claim 2, wherein the absorbedsolvent is at least 5 wt % of the scaffold or tube.